Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2

Zhou, You; Llauradó, Gemma; Orešič, Matej; Hyötyläinen, Tuulia; Orho‐Melander, Marju; Yki‐Järvinen, Hannele

doi:10.1016/j.jhep.2014.10.010

Cited by 105 publications

(97 citation statements)

References 22 publications

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“…The following frequencies of carriers of risk alleles were detected: zero risk alleles, n = 56; one risk allele, n = 142; two risk alleles, n = 170; three risk alleles, n = 117; four risk alleles, n = 27; five risk alleles, n = 3. fibrosis, in our cohort the TM6SF2 polymorphism was linked solely to the grade of steatosis. Importantly, the presence of variant TM6SF2 might even represent a protective factor against metabolic challenges (9,12,26). Based on our current results, one can still argue that, in comparison to the TM6SF2 and MBOAT7 genotypes, the PNPLA3 p.I148M variant plays a more important role as the determinant of severe hepatic phenotypes ranging from steatosis to fibrosis and cirrhosis.…”

Section: Fig 2 Box-and-whisker Plots Illustrating Liver Function Tementioning

confidence: 60%

“…Liu et al (11) reported that carriers of the minor allele are at risk of increased steatosis and fibrosis. Interestingly, both PNPLA3 and TM6SF2 variants have been associated with "metabolically silent" NAFLD; i.e., carriers of the risk genotypes seem to develop NAFLD and its severe forms even in the absence of characteristics commonly associated with fatty liver (5,12). Indeed, numerous genetic studies failed to detect equivocal evidence for the association between TM6SF2 and PNPLA3 variants and traits such as obesity, insulin resistance, or hyperlipidemia.…”

Section: Characteristics Of the Study Cohortmentioning

confidence: 99%

“…No major association between the risk of PNPLA3, TM6SF2, or MABOT7 genotypes and distorted metabolic status has been described. Because PNPLA3-and TM6SF2-driven steatosis might even be "metabolically silent" (12), the inclusion of these two genotypes in the diagnostic work-up of patients with NAFLD could help, together with a detailed analysis of environmental determinants of fatty liver, to identify individuals at increased risk of liver injury even in the absence of the full ensemble of metabolic traits commonly associated with fatty liver disease. By adding the MBOAT7 polymorphism as the third genetic factor to the clinical work-up of the patients with NAFLD, one could further improve the chance of detecting patients who are at risk of liver fibrosis.…”

Section: Fig 2 Box-and-whisker Plots Illustrating Liver Function Tementioning

confidence: 99%

See 2 more Smart Citations

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Krawczyk

Rau

Schattenberg

et al. 2017

Journal of Lipid Research

181

158

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Section: Fig 2 Box-and-whisker Plots Illustrating Liver Function Tementioning

confidence: 60%

Section: Characteristics Of the Study Cohortmentioning

confidence: 99%

Section: Fig 2 Box-and-whisker Plots Illustrating Liver Function Tementioning

confidence: 99%

See 1 more Smart Citation

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Krawczyk

Rau

Schattenberg

et al. 2017

Journal of Lipid Research

181

158

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“…The mechanism for this interaction between abdominal adiposity and the 167K allele remains unclear and warrants further studies. Some other studies in adults have not confirmed the associations of carrying the 167K allele of the TM6SF2 gene with increased plasma ALT and decreased plasma triglycerides and total and LDL cholesterol (9,14). The lack of these associations has been explained by the small sample sizes in these studies (14).…”

Section: Articlesmentioning

confidence: 75%

Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study

et al. 2016

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Background: The 167K allele in the TM6SF2 gene has been suggested to protect against cardiovascular disease at the cost of developing nonalcoholic fatty liver disease in adults. Methods: We performed a cross-sectional study in a population sample of 462 Caucasian children aged 6-9 y, genotyped the polymorphism using HumanCoreExome BeadChip, and assessed several cardiometabolic risk factors. results: The 51 (11%) carriers of the 167K allele had higher plasma alanine aminotransferase (ALT) (20.8 vs. 18.4 U/l, P = 0.011) but lower plasma triglycerides (0.54 vs. 0.61 mmol/l, P = 0.024), total cholesterol (4.08 vs. 4.30 mmol/l, P = 0.016), and low-density lipoprotein (LDL) cholesterol (2.22 vs. 2.38 mmol/l, P = 0.012) than the 411 noncarriers. In factor analysis, the first factor was heavily loaded by plasma ALT (factor loading 0.63), triglycerides (−0.82), LDL cholesterol (−0.71), and waist circumference (0.61) in the carriers but not in the noncarriers. conclusions: The carriers of the 167K allele have higher plasma ALT but lower plasma triglycerides and total and LDL cholesterol than the noncarriers already in childhood. n onalcoholic fatty liver disease (NAFLD), recognized as the hepatic manifestation of the metabolic syndrome (1), is the most common liver disease not only in adults (2) but also in children (3). Increased liver fat content is typically associated with the overproduction of triglyceride-rich very-lowdensity lipoprotein particles from the liver due to the reduced insulin-induced suppression of very-low-density lipoprotein production that leads to hypertriglyceridemia and decreased plasma levels of high-density lipoprotein (HDL) cholesterol (1). NAFLD has been related to increased cardiovascular morbidity and mortality that has been suggested to be partly explained by hypertriglyceridemia and decreased plasma HDL cholesterol levels (2).A recent exome-wide association study showed that adults with a cytosine-to-thymine substitution which replaces glutamate with lysine at residue 167 (E167K polymorphism) in the TM6SF2 gene had increased hepatic triglyceride content and increased plasma levels of alanine aminotransferase (ALT) but decreased plasma levels of triglycerides and low-density lipoprotein (LDL) cholesterol (4). The carriers of the 167K allele were found to have a loss of function of the TM6SF2 that reduces the ability of the liver to export triglycerides in verylow-density lipoprotein particles to circulation that explains the increased liver fat content and the decreased plasma levels of triglycerides among the carriers (5). Consistent with these findings, other studies in adults have shown that the carriers of the 167K allele are more susceptible to NAFLD and liver fibrosis (6-9) but have a lower risk of developing cardiovascular disease that is partly explained by lower plasma total cholesterol levels among the carriers (7,10).A recent study in obese children provided further evidence for the finding in adults that the carriers of the 167K allele in the TM6SF2 gene have a higher liver fat ...

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“…In carriers of the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15% of all individuals), the risk of steatosis [48], and fibrosis [50,51] and HCC [52] are increased while the risk of CVD is even decreased [51]. Serum triacylglycerol and LDL-cholesterol are lower and insulin sensitivity unaltered [48,51,53].…”

Section: Heterogeneity Of Nafld: Nafld But No Metabolic Syndromementioning

confidence: 99%

Diagnosis of non-alcoholic fatty liver disease (NAFLD)

Yki‐Järvinen

2016

Diabetologia

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Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2

Abstract: We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content.

Cited by 105 publications

References 22 publications

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study

Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study

Diagnosis of non-alcoholic fatty liver disease (NAFLD)

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